Abstract Alzheimer's disease (AD) is the most common cause of dementia, and the most common neurodegenerative disease worldwide, affecting 1 in 8 individuals over 65 years old in the US. Within AD, approximately 40-60% individuals are affected by psychotic symptoms (AD+P), which are associated with more rapid cognitive decline, greater disability, mortality and caregiver burden, resulting in a disproportionately large disease burden. Recent studies indicate a genetic basis for AD+P risk, but the molecular basis of AD+P remains largely uncharacterized, hindering the search for appropriate treatments and novel therapeutics. In this proposal, we seek to systematically dissect the mechanistic basis of AD+P by systematic generation, integration, and experimental dissection of transcriptional and epigenomic phenotypes across two brain regions and four cell types. (1) We profile single-cell RNA-seq and cell-type specific H3K27ac ChIP-seq across 192 post-mortem brain samples, each in two regions across AD patients with psychosis, AD patients with no psychosis, schizophrenia patients with no AD, and control individuals. (2) We integrate the resulting datasets with genetic information and GWAS data to predict driver genes, regions, variants, and pathways underlying AD+P using state-of-the-art machine learning methods for causality, mediation analysis, and genetic Bayesian fine- mapping. (3) We use our computational predictions to guide a systematic dissection of the molecular underpinnings of AD+P using a modular and programmable CRISPR-Cas9 methodology in iPSC lines to modulate regulatory elements, genes and alleles, and measure the resulting molecular and cellular phenotypes in cell-autonomous and non-autonomous phenotypes. If successful, this ambitious proposal has the potential to provide the first mechanistic insights on the development of psychotic symptoms in AD+P and/or P-AD, reveal functional risk variants and target genes for therapeutic intervention that will likely influence clinical management in order to alleviate the personal and societal burden associated with these disorders.